Many classes of molecules having diverse structural characteristics elicit a sweet taste. We have chosen to investigate the dipeptide sweeteners in an attempt to evolve a unified theory of predictive value which will correlate structure to taste. Ultimately we hope to design sweeteners which are devoid of adverse pharmacological effects. The dipeptide sweeteners were chosen for this study because of the relative ease of access to analogs and because of the existing, extensive catalog of analogs from which to work. Our research has attempted to show why these molecules are sweet. We initially proposed a topochemical model for the sweeteners (and conversely the sweet-tase receptor in the taste buds) based upon a polar and a hydrophobic interaction. We have synthesized several peptide sweeteners including a series of aspartylphenylglycine esters and a series of aspartylaminomalonic acid diesters which are very sweet. In an effort to test our model, we also synthesized a topochemical analog of the prototype dipeptide sweetener, aspartylphenylalanine methyl ester. This analog N-alpha-(2-benzylmalonic acid monomethyl ester)-alpha, beta-diaminopropionic acid, proved to be tasteless. Since the analog incorporates all of the peripheral characteristics of the prototype but involves a change in the amide linkage, we interpreted these tests to demonstrate the involvement of the amide linkage in binding. Consequently, we are now developing a three-point model attachment model to explain the sweetness of these peptide derivatives. This three-point model involves two polar binding sites and one hydrophobic interaction. We plan to synthesize a series of compounds designed to prove the existence of the third interaction site and to probe the topochemical requirement of the hydrophobic portion of the sweeteners molecule.